English

• Diarylmethanols are an important class of building blocks widely found in natural products^[1] and pharmaceutical compounds^[2], which are generally produced from the direct addition of aldehydes with organometallic reagents such as organo-lithium, -magnesium, and -zinc. However, the use of these active organometallic species would suffer from some troubles because they are either incompatible with many functional groups or sensitive to air and moisture. As a counterpart of the above-mentioned organometallic reagents, organo-boron compounds display excellent tolerance of functional groups and stability to air/moisture. Since the first report on Rh-catalyzed addition of boronic acids to aldehydes by the Miyaura group in 1998^[3], numerous catalysts for such a transformation have been developed, including rhodium^[4], palladium^[5], platinum^[6], ruthenium^[7] and nickel-based^[8] catalysts. Despite the impressive advances, further improvement on those protocols remains urgently needed: it was recognized that rhodium, palladium, platinum, or ruthenium belongs to precious metals; on the other hand, although nickel is cheap, the Ni⁰ species are hard to handle in practice due to its air-/moisture-sensitivity and toxicity. Accordingly, it is still highly desired to develop the nickel(Ⅱ)-based catalyst systems for this addition reaction. To our knowledge, there have been few successful cases in this regard. For instance, Bao group in 2009 disclosed one publication involving the utility of divalent nickel source, Ni(ClO₄)₂, as pre-catalyst^[9].Herein, we wish to report a new protocol concerning a simple nickel(Ⅱ) catalyst system for the addition of arylboronic acids to arylaldehydes.

  1.   Experimental

  1.1   General remarks

  All reactions were carried out under nitrogen atmosphere with oven-dried glassware. Toluene, THF and dioxane were distilled from sodium/benzop-henone before use. Potassium carbonate, potassium phosphate, cesium fluoride and potassium tert-butoxide were commercially available and used with finely-ground powder. Column chromatography was performed on silica gel (200~300 mesh). All yields were referred to isolated yield (average of two runs) of compounds estimated to be >95% pure as determined by ¹H NMR. All the products were characterized by melting points (for solid samples), MS, ¹H and ¹³C NMR. Melting points were measured with a X-4 micro melting point apparatus and uncorrected.

  General procedure for Ni-catalyzed 1, 2-addition of aryl aldehydes with arylboronic acids: An oven-dried 25-mL three-necked flask was charged with K₃PO₄ (2.5mmol), NiCl₂(PPh₃)₂(0.05mmol) and IPr·HCl (0.1mmol). Then the aryl aldehyde (1.0mmol) (if solid) and the arylboronic acid (1.5mmol) were added. The flask was evacuated and backfilled with nitrogen, with the operation being repeated twice. Dried toluene (5mL) and the aryl aldehyde (1.0mmol) (if liquid) were added via syringe at this time. The reaction mixture was heated in an oil bath at 110℃ for 8h and then allowed to cool to room temperature; it was then filtered through a silica-gel pad that was washed with ethyl acetate. The combined organic phases were evaporated under reduced pressure and the residue was purified by silica-gel column chromatography to give the desired products.

  1.2   Characterization data of the products

  Diphenyl-methanol (Tab. 2, entry 1). White solid: mp 66~68℃. ¹H NMR (400MHz, CDCl₃) δ: 7.38~7.30 (m, 8H), 7.27~7.23 (m, 2H), 5.83 (s, 1H), 2.14 (s, 1H); ¹³C NMR (101MHz, CDCl₃) δ: 143.9, 128.6, 127.6, 126.6, 76.3; MS (EI) m/z: 284 [M⁺].

  Table 1

  

  表 1  Ni催化的苯甲醛与苯硼酸的1, 2加成条件优化

  Table 1.  Screening of conditions for Ni-catalyzed 1, 2-addition of benzaldehyde with phenylboronic acid^a

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  Entry	[Ni(Ⅱ)]	Ligand(mol%)	Base	Solvent	Yield b(%)
  1	Ni(PPh3)2(1-naphthyl)Cl	PPh3 (10)	K3PO4	toluene	11
  2	Ni(PPh3)2(1-naphthyl)Cl	PCy3 (10)	K3PO4	toluene	32
  3	Ni(PPh3)2(1-naphthyl)Cl	DPPFc (5)	K3PO4	toluene	15
  4	Ni(PPh3)2(1-naphthyl)Cl	IPr.HCld (10)	K3PO4	toluene	49
  5	NiCl2·6H2O	IPr.HCl (10)	K3PO4	toluene	trace
  6	Ni(acac)2	IPr.HCl (10)	K3PO4	toluene	8
  7	NiCl2(PPh3)2	IPr.HCl (10)	K3PO4	toluene	81
  8	NiCl2(PPh3)2	IPr.HCl (10)	CsF	toluene	67
  9	NiCl2(PPh3)2	IPr.HCl(10)	K2CO3	toluene	9
  10	NiCl2(PPh3)2	IPr.HCl(10)	t-BuOK	toluene	7
  11	NiCl2(PPh3)2	IPr.HCl(10)	K3PO4	THF	trace
  12	NiCl2(PPh3)2	IPr.HCl(10)	K3PO4	dioxane	trace
  13	NiCl2(PPh3)2	IPr.HCl(10)	K3PO4	toluene	56e
  14	NiCl2(PPh3)2	IPr.HCl(10)	K3PO4	toluene	0f
  15	NiCl2(PPh3)2	IPr.HCl(0)	K3PO4	toluene	0
  aReaction conditions: benzaldehyde (1.0mmol), phenylboronic acid (1.5mmol), catalyst (5(mol)%), base (2.5mmol), solvent (5.0mL), 110℃, 8h, N2; bIsolated yields; c DPPF: 1, 1'-bis(diphenylphosphino)ferrocene; d IPrHCl: 1, 3-bis(2, 6-diisopropylphenyl)imidazolium chloride; e 90℃; f NiCl2(PPh3)2 (0(mol)%).

  Table 2

  

  表 2  Ni催化的芳基醛与芳基硼酸的1, 2加成

  Table 2.  Ni-catalyzed 1, 2-addition of aryl aldehydes with arylboronic acids ^a

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  Phenyl-(3, 4, 5-trimethoxy-phenyl)-methanol (Tab. 2, entry 2). White solid: mp 109~111℃. ¹H NMR (400MHz, CDCl₃) δ: 7.40~7.28 (m, 5H), 6.61 (s, 2H), 5.78 (s, 1H), 3.83 (s, 9H); ¹³C NMR (CDCl₃, 100MHz): δ 153.1, 143.7, 139.6, 137.1, 128.4, 127.5, 126.5, 103.5, 76.1, 60.7, 56.0; MS (EI) m/z: 274 [M⁺].

  Acetic acid 4-(hydroxy-phenyl-methyl)-benzyl ester (Tab. 2, entry 3). Colorless oil. ¹H NMR (400MHz, CDCl₃) δ: 7.40~7.31 (m, 8H), 7.28~7.26 (m, 1H), 5.85 (s, 1H), 5.08 (s, 2H), 2.08 (s, 3H); ¹³C NMR (101MHz, CDCl₃) δ: 171.0, 144.0, 143.7, 135.2, 128.6, 128.5, 127.7, 126.8, 126.6, 76.0, 21.0; MS (EI) m/z: 256 [M⁺].

  (4-Hydroxymethyl-phenyl)-phenyl-methanol (Tab. 2, entry 4). White solid: mp 105~107℃. ¹H NMR (400MHz, CDCl₃) δ: 7.38~7.26 (m, 9H), 5.84 (s, 1H), 4.66 (s, 2H); ¹³C NMR (101MHz, CDCl₃) δ: 143.9, 143.4, 140.2, 128.6, 127.7, 127.3, 126.8, 126.6, 76.1, 65.1; MS (EI) m/z: 214 [M⁺].

  (4-Dimethylamino-phenyl)-phenyl-methanol (Tab. 2, entry 5). White solid: mp 58~60℃. ¹H NMR (400MHz, CDCl₃) δ: 7.40~7.35 (m, 2H), 7.32 (t, J=7.6 Hz, 2H), 7.26~7.21 (m, 3H), 6.70 (d, J=8.0 Hz, 2H), 5.78 (s, 1H), 2.93 (s, 6H); ¹³C NMR(101MHz, CDCl₃) δ: 150.2, 144.4, 132.2, 128.6, 127.8, 127.2, 126.4, 112.6, 76.0, 40.7; MS (EI) m/z: 227 [M⁺].

  Naphthalen-1-yl-(3, 4, 5-trimethoxy-phenyl)-methanol (Tab. 2, entry 8). Colorless oil. ¹H NMR (400MHz, CDCl₃) δ: 8.08~8.05 (m, 1H), 7.60~7.53 (m, 4H), 7.87~7.84 (m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.47~7.43 (m, 3H), 6.62 (s, 2H), 6.44 (s, 1H), 3.81 (s, 3H), 3.75 (s, 6H), 2.56 (s, 1H); ¹³C NMR (101MHz, CDCl₃) δ: 153.3, 138.9, 138.7, 137.3, 134.0, 130.9, 128.8, 128.6, 126.3, 125.7, 125.4, 124.7, 123.9, 104.2, 73.6, 60.9, 56.1; MS (EI) m/z: 324 [M⁺].

  (6-Methoxy-naphthalen-2-yl)-phenyl-methanol (Tab. 2, entry 9). White solid: mp 65~67℃. ¹H NMR (400MHz, CDCl₃) δ: 7.80 (s, 1H), 7.73~7.68 (m, 2H), 7.41 (t, J=8.0 Hz, 3H), 7.34 (t, J=7.2 Hz, 2H), 7.28 (d, J=7.2 Hz, 1H), 7.16~7.11 (m, 2H), 5.97 (s, 1H), 3.91 (s, 3H), 2.34 (s, 1H); ¹³C NMR (101MHz, CDCl₃) δ: 157.7, 143.8, 139.0, 134.0, 129.6, 128.7, 127.5, 127.2, 126.7, 125.4, 125.0, 118.9, 105.8, 76.2, 55.3; MS (EI) m/z: 264 [M⁺].

  (4-Fluoro-phenyl)-(6-methoxy-naphthalen-2-yl)-methanol (Tab. 2, entry 10). White solid: mp 105~107 ⁰C. ¹H NMR (400MHz, CDCl₃) δ: 7.77 (s, 1H), 7.71 (t, J=9.6 Hz, 2H), 7.40~7.35 (m, 3H), 7.16~7.11 (m, 2H), 7.02 (d, J=8.8 Hz, 2H), 5.96 (s, 1H), 3.91 (s, 3H), 2.26 (s, 1H); ¹³C NMR (101MHz, CDCl₃) δ: 162.1 (d, J=244.2 Hz), 157.9, 139.6, 138.8, 134.1, 129.6, 128.7, 128.4 (d, J=8.0 Hz), 127.3, 125.2, 125.0, 119.1, 115.3 (d, J=21.2 Hz), 105.8, 75.6, 55.3; MS (EI) m/z: 282 [M⁺].

  (6-Methoxy-naphthalen-2-yl)-(4-trifluoro-methyl-phenyl)-methanol (Tab. 2, entry 11). White solid: mp 113~115^oC. ¹H NMR (400MHz, CDCl₃) δ: 7.76 (s, 1H), 7.71 (t, J=8.0 Hz, 2H), 7.60~7.53 (m, 4H), 7.35 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 6.00 (s, 1H), 3.91 (s, 1H), 2.21 (s, 1H); ¹³C NMR (101MHz, CDCl₃) δ: 158.1, 147.6, 138.3, 134.3, 129.6, 128.7, 127.6, 126.8, 125.5, 125.2, 119.3, 105.8, 75.9, 55.4; MS (EI) m/z: 332 [M⁺].

  2.   Results and Discussion

  1, 2-addition of benzaldehyde with phenyl-boronic acid were chosen to screen the reaction conditions. The results are summarized in Tab. 1. Initially, compared with phosphine ligands, the bulky and strongly donating IPr·HCl were proved to be the most effective ligand (Tab. 1, entries 1~4). Then, various common nickel(Ⅱ) sources were investigated (entries 5~7). The results clearly indicated that Ni(PPh₃)₂Cl₂ was superior to other nickel(Ⅱ) sources, providing the desired product in 81% yield (entry 7). For other bases such as CsF, K₂CO₃ and t-BuOK, the reaction just afforded disappointing results (entries 8~10). Toluene appeared to be the solvent of choice for the reaction and far superior to ethereal solvents such as THF (entry 11) and dioxane (entry 12). Meanwhile, lowering the reaction temperature caused a remarkable decrease in the yield (entry 13 vs. 7). Moreover, no desired product was observed without NiCl₂(PPh₃)₂ or IPr·HCl (entries 14~15). Therefore, our standard conditions were set up as entry 7 in Tab. 1.

  Under the optimized conditions, the scope and limitations of the coupling reaction were investigated, and the results were summarized in Tab. 2. Generally, electron-neutral (Tab. 2, entry 1) and -rich (entries 2~5, 8 and 9 except for entry 5) aryl aldehydes showed good to excellent reactivity and provided desired products in high yields. Interestingly, some sensitive functional groups such as ester (entry 3) and hydroxyl (entry 4) were tolerated under the mild reaction conditions. Neither aliphatic aldehyde nor ketone was suitable for this reaction and no product was obtained (entries 6, 7). For arylboronic acid substrates, the electronic effect showed a remarkable influence on the outcome. Electron-deficient arylboronic acid performed poorly under the standard conditions, but the outcome was improved by increasing its amounts (entries 10, 11). The reaction was unsuccessful using arylboronic acids with electron-rich groups (entries 12, 13).

  3.   Conclusions

  In summary, we have developed a new protocol for the addition reaction of arylboronic acids with arylaldehydes utilizing a simple, cheap, and practical NiCl₂(PPh₃)₂/IPr·HCl catalyst system. Further work to expand the scope of substrates and elucidate the mechanistic details is currently underway in our laboratory.

  
  
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• Table 1.  Screening of conditions for Ni-catalyzed 1, 2-addition of benzaldehyde with phenylboronic acid^a

  Entry	[Ni(Ⅱ)]	Ligand(mol%)	Base	Solvent	Yield b(%)
  1	Ni(PPh3)2(1-naphthyl)Cl	PPh3 (10)	K3PO4	toluene	11
  2	Ni(PPh3)2(1-naphthyl)Cl	PCy3 (10)	K3PO4	toluene	32
  3	Ni(PPh3)2(1-naphthyl)Cl	DPPFc (5)	K3PO4	toluene	15
  4	Ni(PPh3)2(1-naphthyl)Cl	IPr.HCld (10)	K3PO4	toluene	49
  5	NiCl2·6H2O	IPr.HCl (10)	K3PO4	toluene	trace
  6	Ni(acac)2	IPr.HCl (10)	K3PO4	toluene	8
  7	NiCl2(PPh3)2	IPr.HCl (10)	K3PO4	toluene	81
  8	NiCl2(PPh3)2	IPr.HCl (10)	CsF	toluene	67
  9	NiCl2(PPh3)2	IPr.HCl(10)	K2CO3	toluene	9
  10	NiCl2(PPh3)2	IPr.HCl(10)	t-BuOK	toluene	7
  11	NiCl2(PPh3)2	IPr.HCl(10)	K3PO4	THF	trace
  12	NiCl2(PPh3)2	IPr.HCl(10)	K3PO4	dioxane	trace
  13	NiCl2(PPh3)2	IPr.HCl(10)	K3PO4	toluene	56e
  14	NiCl2(PPh3)2	IPr.HCl(10)	K3PO4	toluene	0f
  15	NiCl2(PPh3)2	IPr.HCl(0)	K3PO4	toluene	0
  aReaction conditions: benzaldehyde (1.0mmol), phenylboronic acid (1.5mmol), catalyst (5(mol)%), base (2.5mmol), solvent (5.0mL), 110℃, 8h, N2; bIsolated yields; c DPPF: 1, 1'-bis(diphenylphosphino)ferrocene; d IPrHCl: 1, 3-bis(2, 6-diisopropylphenyl)imidazolium chloride; e 90℃; f NiCl2(PPh3)2 (0(mol)%).

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  Table 2.  Ni-catalyzed 1, 2-addition of aryl aldehydes with arylboronic acids ^a

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•